Synthesis of 2-substituted-5-methyl-pyridines

ABSTRACT

A process for the synthesis of compounds which are known intermediates for the pyridyloxyphenoxy herbicides as well as intermediates used in the process. Propionaldehyde and an acrylic compound, two readily available starting materials, are reacted to form a 2-formylpentanoic compound which is cyclized to a dihydro pyridone which is then oxidized to the 2-hydroxy pyridine. The hydroxypyridine may be halogenated to a 2-halopyridine.

BACKGROUND OF THE INVENTION

Various 4-(5-halomethyl-2-pyridyloxy)phenoxy compounds are known to beuseful as herbicides as disclosed in European Published patentapplication No. 483, United Kingdom patent specification Nos. 1,599,121and 1,599,126 and U.S. Pat. Nos. 4,184,041 and 4,317,913. For example,butyl 2-[4-(5-trifluoromethyl-2-pyridyloxy)phenoxy]propionate which isalso known as fluazifopbutyl is an effective grass herbicide which canbe used in fields where broad-leaved crops such as cotton and soybeansare cultivated. Important starting materials for such pyridyloxy phenoxycompounds are the 2-halo-5-trichloromethylpyridines such as2-chloro-5-trichloromethylpyridine described in U.S. Pat. No. 4,317,913.Such 2-halo-5-trichloromethylpyridines, in turn, may be prepared bychlorinating, under ultraviolet light irradiation, a2-halo-5-methylpyridine as described in U.S. Pat. No. 4,152,328.

An object of the present invention is an efficient, economical andreliable synthesis of 2-halo-5-methylpyridines as well as intermediatesused in the synthesis.

A further object of the present invention is a method for preparing2-halo-5-methylpyridines without utilizing pyridine, and in particular3-picoline, starting materials to thus avoid the problems of byproductformation in the halogenation reaction to yield (I) wherein X ishalogen.

SUMMARY OF THE INVENTION

The present invention comprises a method for the synthesis of a5-methylpyridine of the formula (I): ##STR1## wherein X is a halogen orhydroxy, by condensing the acyclic aliphatic starting materialspropionaldehyde and an acrylic ester, amide or nitrile to form agamma-methyl gamma-aldehydo ester, amide or nitrile which ester may thenbe aminated with a nitrogen source such as an amine or ammonium compoundto form a dihydro-5-methyl-2-pyridone, which amide may be thermallycyclized and which nitrile may be converted to the pyridone via acidcatalysis. The pyridone may then be oxidized to the compound of formula(I) wherein X is hydroxy which may be halogenated to the compound offormula (I) wherein X is halo. Also part of the present invention arethe individual process steps and novel intermediates formed in thesynthesis.

DETAILED DESCRIPTION OF THE INVENTION

In the first step (a) of the process of the present invention,propionaldehyde of the following formula (II) is reacted in a Michaeltype addition with an acrylic compound of the following formula (III):##STR2## wherein Y is a moiety of the formula --COOR, --CONH₂ or --CNand R is an organic moiety, to produce a pentanoic aldehyde of thefollowing formula (IV): ##STR3## R, in particular, may be a substitutedor unsubstituted alkyl or aryl group although a wide range of moietiesmay be used since the --OR function is removed in the following step.Thus, R may be any grouping which is stable to the Michael additionconditions used and which is removable as the --OR moiety uponnucleophilic attack by a nitrogen on the --COOR group. Particularexamples of R are alkyl of about 1 to 6 carbons, e.g., methyl or ethyl,aryl of about 6 to 10 carbons or arylalkyl of about 1 to 8 carbons inthe alkyl portion and about 6 to 10 carbons in the aryl portion, whicharyl or aryl portion may be substituted by groups such as lower alkyl orhalogen. The Michael addition may be conducted as known in the art suchas at a temperature of about 0° to 100° C., neat or in the presence ofan inert solvent and optionally in the presence of a reaction catalystsuch as strong base. The compound of formula (IV) may be recovered byextraction, chromatography or distillation.

Preferably, the first step of the process is conducted in three stagesby the use of protection and deprotection reactions which serve toactivate the propionaldehye for the Michael addition, to minimize sidereactions and to avoid the use of strong reagents and catalysts. Thethree stages of the first step involve (i) reacting propionaldehye witha secondary amine of the formula HNR¹ R², wherein R¹ and R² areindependently organic moieties which may be attached to each other toform a ring, to form, directly or through an intermediate aminal theenamine of the following formula (VII): ##STR4## In particular, valuesof R¹ and R² include individual substituted and unsubstituted alkyl ofabout 1 to 6 carbons such as ethyl and butyl and, when R¹ and R² areconnected, substituted and unsubstituted heterocyclic rings such as 5-or 6-membered heterocyclic rings, e.g., to define the secondary aminespyrrolidine, piperidine and morpholine. The first stage (i) may beconducted at about -10° to 35° C. preferably in the presence of analkali or alkaline earth metal carbonate, sulfate, halide or oxide,e.g., calcium sulfate, magnesium sulfate, calcium chloride, sodiumsulfate, magnesium oxide, potassium carbonate, calcium oxide or evenmolecular sieves, as disclosed by D. Roelofsen et al. in Recueil, Vol.91, pages 605-610 (1972), with at least two moles of HNR¹ R² per mole ofpropionaldehyde. The secondary amine is used in excess in view of theintermediate formation of an aminal of the formula CH₃ CH₂ CH(NR¹ R²)₂which is then heated to form the enamine of formula (VII) and distil offthe excess HNR¹ R² which is released with formation of the double bond.Thus, the aminal may be heated to about 75° to 100° C. at a vacuum ofabout 40 to 100 mm of Hg. According to this aspect of the presentinvention, the enamine of formula (VII) and the secondary amine HNR¹ R²are coformed from the aminal and preferably, the HNR¹ R² will beseparated from the enamine at this point by fractional distillation. Ifthe secondary amine has a boiling point close to the enamine, e.g., ifthe secondary amine is morpholine, the distillation should be monitoredto avoid codistillation of the two products and/or an incompletereaction of the aminal. If the aminal is obtained in whole or in part atthis point, such may be taken on to the cyclobutane of formula (VIII) asdescribed below. This monitoring can be carried out by gas liquidchromatography and % nitrogen by elemental analysis. Disclosures of suchenamine formations include C. Mannich and H. Davidsen in Ber., vol. 69,pages 2106-2112 (1936); G. Opitz et al. in Ann., Vol. 623, pages 112-117(1959); P. deBenneville et al. in J. American Chemical Society, Vol. 72,pages 3073-3075 (1950); R. Dulou et al. in Bull. Chem. Soc. France,pages 967-971 (1960); G. Kalaus in Ber., Vol. 114, pages 1476-1483(1981); and E. Benzing U.S. Pat. No. 3,074,940.

In the second stage (ii) of the first step of the invention, the enamineof formula (VII) is reacted with the acrylic compound of formula (III)to yield the compound of the following formula (VIII): ##STR5## whereinY, R¹ and R² are as defined above for formulae (III) and (VII). Thecompound of formula (VIII) may exist to a limited extent in the form ofthe open chain enamine of the structure (R¹ R² N)HC═CHCH₃ (CH₂)₂ Y. Thesynthesis of cyclobutanes of the formula (VIII) type is described indetail by I. Fleming et al. in the Journals of the Chemical Society,pages 2165-2174 (1964) and in U.S. Pat. Nos. 3,051,622; 3,133,924;3,369,024; 3,481,936; and 3,481,939. The reaction may be carried outneat or in the presence of a nitrile, ether, ester, halogenated alkaneor ketone solvent, e.g., acetonitrile, although a neat reaction ispreferred in view of simplicity. The reaction may be carried out at roomtemperature up to the boiling point of the acrylic compound of formula(III), e.g., up to about 170° C., with the higher temperatures of thisrange being advantageously used to complete the reaction. The enamine offormula (VII) may be cooled to about -5° to 20° C. with dropwiseaddition of the acrylic compound of formula (III) followed by warming tothe range of room temperature to about the boiling point of the acryliccompound.

The third stage (iii) of the first step of the invention process is thehydrolysis of the compound of formula (VIII) to the aldehyde of formula(IV) with recovery of one mole of the secondary amine HNR¹ R². Thereaction may be conducted in an aqueous acidic medium such as in thepresence of an aqueous organic or mineral acid, such as acetic,sulfuric, hydrochloric, phosphoric or toluene sulfonic acids, optionallywith a solvent such as those listed for the second stage (ii) of thefirst step, at a temperature of about 25° to 105° C. at a pH of about1.5 to 4.5. The solvent for this reaction may advantageously be thatused in stage (ii) whereby the product of stage (ii) need not bepurified but rather may be simply carried forward in its crude statewith solvent. However, a solvent other than the aqueous acidic reactionmedium need not be present. The aldehyde of formula (IV) may berecovered by extraction of the aqueous acid solution containing HNR¹ R²with a neutral organic solvent such as ethyl acetate or methylenechloride. Alternatively, the third stage hydrolysis (iii) may beconducted under basic conditions and in the event of saponification ofthe ester, the acid is formed, i.e., the compound of formula (IV)wherein Y is --COOR and R is hydrogen, and such may be cyclized to thedihydropyridone of formula (V) as explained below. A disclosure ofreactions leading to (IV) wherein Y is --COOCH₃ was made by W. Pirkle etal. in the Journal of Organic Chemistry, Vol. 40, pages 1617-1620 (1975)with similar reactions being described by G. Stork in the Journal of theAmerican Chemical Society, Vol. 85, pages 207-221 (1963). The reactionof acrylonitrile, i.e., compound (III) where Y═CN, with the pyrrolidineenamine of n-heptaldehyde is described by Ross C. Terrell, Ph.D. ThesisColumbia University (1955 ) as yielding α-cyanoethyl-n-heptaldehyde andcompound (IV) where Y═CN may be produced in a similar manner.

In the second step (b) of the process of the invention when Y═COOR, thealdehyde of formula (IV) is reacted with an amine or ammonium salt toform the dihydropyridone of the following formula (V): ##STR6## Thecyclization in step (b) may be carried out with a nitrogen source suchas an amine or ammonium salt, with specific examples being ammoniumcarbamate, ammonium carbonate, ammonium hydroxide, ammonia, ammoniumbicarbonate, ammonium acetate or ammonium orthophosphate. In general, anammonium salt of a weak acid such as phosphoric, carbonic or acetic acidis preferred. The reaction may be carried out neat or in a solvent,e.g., a high boiling solvent, for one or both reactants such as acarboxylic acid, e.g., acetic acid, an alkanol which use is lesspreferred, e.g., ethanol, an aromatic hydrocarbon compound, e.g.,benzene or toluene, a halogenated aromatic hydrocarbon, e.g., a mono-,di- or tri-chlorobenzene, or a ketone, e.g., methyl ethyl ketone, methylisobutyl ketone and disobutyl ketone. The temperature of the cyclizationreaction will vary depending on the particular nitrogen source used andthe solvent but is, in general, from about room temperature up to theboiling point of any solvent or reactant utilized, e.g., from about 25°to 150° C.

In the second step (b) of the process of the invention when Y═CONH₂ thealdehyde of Formula (IV) is thermally cyclized at a temperature of about100° to 200° C. neat or in a high boiling solvent such as aromatichydrocarbon compound, e.g., benzene, xylene or acrylamide, or ahalogenated aromatic hydrocarbon, e.g., a mono-, di- ortri-chlorobenzene and the pyridone of formula (V) may be recovered bystandard techniques such as distillation or extraction.

In the second step (b) when Y═CN, the aldehyde (IV) is converted to thepyridone (V) by acid catalysis, e.g., with hydrogen halide such as HCl,sulfuric acid, phosphoric acid or a sulfonic acid at a temperature ofroom temperature to about 100° C. neat or in a solvent such as ahalogenated hydrocarbon. Such reaction conditions are described by N. P.Susherina et al. in Chemical Abstracts, Vol. 55 7410e, by A. I. Meyersin J. Organic Chemistry, Vol. 29, pages 1435-1438 (1964) and in GermanOffenlegundschrift No. 2,245,097 (Mar. 21, 1974).

In one aspect of the invention, the cyclization step (b) may beconducted in two stages by (iv) dimerizing the aldehyde of formula (IV)where Y═COOR by reaction with excess ammonia or other nitrogen source toyield the pyridone adduct of the following formula (X): ##STR7##followed by (v) pyrolyzing the compound of formula (X) with loss of NH₃at a temperature of about 200° to 300° C. to yield the dihydropyridineof the formula (V).

In the third step (c) of the process of the present invention, thedihydropyridone of formula (V) is oxidized to the pyridone of thefollowing formula (VI): ##STR8##

In one aspect of the present invention, the oxidation step (c) may becarried out by a first stage (vi) comprising dihalogenating the compoundof formula (V) with a halogenating agent such as chlorine, bromine,sulfuryl bromide or sulfuryl chloride in an equimolar to slight molarexcess at about 25° to 40° C. in a solvent such as a halogenatedhydrocarbon, e.g., chloroform or chlorobenzene, to produce the dihalocompound of the following formula (IX): ##STR9## wherein X¹ is a halogenatom, such as chloro or bromo. In a further stage (vii), the dihalocompound of formula (IX) may then be dehydrohalogenated to produce thepyridine of formula (VI) by heating to a temperature of about 100° to170° C. neat or in the presence of a high boiling solvent such aschlorobenzene. In general, the product of the dehydrohalogenation stage(vii) is the hydrohalide salt of the pyridine of formula (VI) which maybe carried on directly to the 5-methylpyridine of formula (I) wherein Xis a halogen, or may be first converted to the free base byneutralization in an aqueous base such as sodium hydroxide or sodiumcarbonate followed by vacuum evaporation and extraction with an organicsolvent such as hot acetone or ethanol. The halogenation of variousdihydro pyridones is described by N. P. Shusherina et al. in ChemicalAbstracts, Vol. 55 7410f (1961), Vol. 60 4101 (1964), vol. 58 9011d and12507h (1963) and by D. Diller et al. in Berichte Vol. 110, pages2956-2957 (1977).

In the dihalogenation stage (vi) used to produce the dihalo compound offormula (IX), several products have been observed which may be readilyconverted to pyridone of formula (VI) together with or separate from thedihalo compound (IX). In particular, the reaction conditions describedabove for stage (vi) have yielded both the hydroxy halo compound of thefollowing formula (XI) when water is present: ##STR10## wherein X² is ahalogen such as bromo or chloro, and the dimeric compound of thefollowing formula (XII): ##STR11## wherein X³ is a halogen such as bromoor chloro. In general, use of lower temperatures for the dihalogenationstage (vi) will produce compound (IX) while higher temperatures, e.g.,about 40° to 80° C. will yield the by-products (XI) and/or (XII). Thus,at a reaction temperature of 40° to 80° C. for 2 hours in toluene with a50% molar excess of sulfuryl chloride, compound (V) may be vacuumevaporated and extracted with toluene to leave insolubles which includethe compound of formula (XI) wherein X² is chloro, m.p. 135° to 142° C.If the same reaction is conducted in chloroform at 30° to 60° C., thecrystaline product contains the dimer of formula (XII) wherein X³ ischloro, m.p. 157° to 159° C. The hydroxy halo compound (XI) and dimericcompound (XII) may be converted to the pyridine (VI) by heating to about175° to 250° C. neat or in the presence of a high boiling solvent. Anadvantage of the invention process that the by-products of this step canbe converted to the next stage product in the same manner as the desiredproduct, i.e., (XI) and (XII) are converted to (VI) in the same manneras (IX) would be.

The oxidation step (c) may also be carried out by reacting thedihydropyridone of formula (V) with a halogenating agent such asN-chloro- or N-bromo-succinimide or 1,3-dichloro- or1,3-dibromo-5,5-dimethylhydantoin which adds halogen at an allylicposition or the position alpha to the carbonyl, i.e., the 3- or4-halo-2-pyridone to yield the compound of the following formula (XIII):##STR12## wherein X⁴ is halogen such as bromo or chloro. The compound offormula (XIII) may then be converted to the pyridine of formula (VI) bythermal elimination of HX⁴.

In the final step (d) of the overall process of the invention, thepyridone (VI) is halogenated with a halogenating agent such as a sulfurhalide, e.g., thionyl chloride, sulfuryl chloride, a carboxylic acidhalide, e.g., phosgene, or a phosphorus halide such as phenylphosphonicdichloride, phosphorus oxychloride or phosphorus pentachloride, in ahigh boiling solvent such as a aromatic hydrocarbon solvent, e.g.,toluene or xylene, or a halogenated aromatic hydrocarbon, e.g.,chlorobenzene, at a temperature of about 90° to 120° C. to yield thecompound of formula (I) wherein X is a halogen, e.g., chloro bromo oriodo. The molar ratio of halogenating agent:compound of formula (VI) mayvary, e.g., a ratio of POCl₃ : (VI) of about 1.5:1 to 4.5:1 or of PCl₅ :(VI) of about 0.3:1 to 0.5:1 may be used. In addition, a combination ofphosphorus halides may be used, e.g., a mixture of POCl₃ and PCl₅ in amolar ratio of 1:0.1 or 1.6:0.45. Thus, the molar ratio of halide atomsin the phosphorous halide:compound of formula (VI) should be about 6:1.The reaction of 2-hydroxy-5-methylpyridine to yield2-chloro-5-methylpyridine is also described by W. Herz et al. in theJournal of Organic Chemistry, Vol. 22, pages 122-125 (1961).

Particular aspects of the process of the present invention which areadvantageous are high yields obtained, the novel skeletal formation of aβ-picoline while simultaneously functionalizing the 2-position with agroup which is readily transformed to chlorine and the in situgeneration of the ammonium compound such as ammonium acetate in theconversion of the compound of formula (IV) to (V).

Also part of the present invention are novel intermediates as describedherein.

In the following Examples and throughout the specification, thefollowing abbreviations are used: °C. (degrees Centigrade); ml(milliliters); g (grams); m (moles); mm (millimeters); GLC (gas liquidchromatography); GC/MS (gas chromatograph-mass spectrometry); IR(infrared); NMR (nuclear magnetic resonance); mp (melting point); bp(boiling point); d₆ -DMSO (deuterated dimethyl sulfoxide); and theconventional symbols for the chemical elements.

EXAMPLE 1 Step (a), stage (i) to yield morpholinopropene of formula(VII) (NR¹ R² ═morpholine)

A 500 ml 4-neck flask was equipped with a stirrer, thermometer, additionfunnel and condenser. To the flask was charged 191.7 g (2.2 m) ofmorpholine and 138.2 g (1 m) of potassium carbonate (anhydrous) and themixture was stirred and cooled to -5° C. with an ice-salt bath. To theflask was added 58 g (1 m) of propionaldehyde over a period of 55minutes at a pot temperature of -5° C. The temperature was then allowedto rise to 25° to 27° C. and the reaction was continued for 2 hours at25° C. The product was filtered and the filter cake washed with four 15ml washes of toluene. The fitrate was heated under vacuum whilemorpholine was stripped using a 1 foot Vigreux column. This treatmentwas carried out at an oil bath temperature of 85° to 112° C., a pottemperature of 70° to 90° C., a vapor temperature of 41° to 58° C. andat a pressure of approximately 35 to 40 mm of Hg. The vacuum strippingwas carried out until 133.3 g of product was obtained as a residue. GLCand GC/MS established that the predominant product was4-(2-propenyl)morpholine.

¹³ C NMR in d₆ --DMSO (in δ units):15.2 (CH₃) 95.1 (CH₃ --CH)═; 140.8(--CH═CH--); 49.4 (--N(--CH₂ --)₂); and 66.1 (O(--CH₂ --)₂).

EXAMPLE 2

To a thin slurry of 191.7 g (2.2 m) of morpholine and 84.0 g (1.5 m) ofcalcium oxide was added dropwise 58 g (1 m) of propionaldehyde over a 30minute period at 15° C. The reaction was mildly exothermic and somecooling was applied. The slurry was filtered after 30 minutes reactiontime at 25° C. and the filter cake was washed with two 40 ml washes ofmorpholine. The filtrate was gradually heated to 75° to 85° C. undervacuum and then held at 85° C. pot temperature and a pressure of 40 mmof Hg vacuum over 2 hours while distilling morpholine in a Vigreuxcolumn. The product pot residue weighed 116.6 g.

EXAMPLE 3 Step (a), stage (ii) to yield acrylic compound of formula(VIII) (Y═COOR; R═CH₃ ; NR¹ R² ═morpholine)

A solution of 40 g of crude morpholinopropene produced in Example 1 in175 ml of acetonitrile is cooled to -2° C. in an ice-salt bath andtreated with a solution of 30.5 g (0.35 m) of methylacrylate in 70 ml ofacetonitrile dropwise over a period of 20 minutes at -2° to 0° C. Thetemperature of the solution is then gradually raised and held at 66° to76° C. for 17 hours. At that point, a predominate product peak can bedetected by GLC together with a smaller unidentified peak while at thesame time, the morpholinopropene peak has almost completely disappeared.The methyl 3-methyl-2-(4-morpholinyl)cyclobutane carboxylate wascharacterized by GC/MS and NMR.

¹³ C NMR in d₆ --DMSO (in δ units):66.3 (O(--CH₂ --)₂); 50.2 (--N(--CH₂--); 70.8 (N--CH); 31.0 (CH₃ --CH); 26.2 (cyclobutane--CH₂ --); 39.1(CH--COOCH₃) 174.1 (--COOCH₃); 51.4 (--COOCH₃); and 20.6 (CH--CH₃).

EXAMPLE 4

To 63.5 g of the crude morpholinopropene product of Example 2 wasgradually added 45.7 ml (0.51 m) of methyl acrylate at room temperature.The reaction mixture was then heated to 80° C. until the reaction wascomplete in 7 hours as determined by GLC. The yield of product was 106.4g with no loss during vacuum stripping to remove unreacted acrylate at 1hour at 55° C. under a pressure of 50 mm of Hg.

EXAMPLE 5 Step (a), stage (iii) to yield methyl 4-formylpentanoate offormula (IV) (Y═COOR; R═CH₃)

A solution of 18 g (0.3 m) of acetic acid in 120 ml of water is added tothe crude morpholino cyclobutane carboxylate ester product of Example 3and the reaction mixture is heated at 70° to 79° C. for 5 hours. Theproduct solution is cooled to room temperature, diluted with 150 ml ofwater and extracted 3 times with ethyl acetate, 100 ml each wash. Theextracts were washed 2 times with dilute sodium chloride brine solutionand methyl 4-formylpentanoate is obtained after vacuum stripping at 60°to 70° C. and a moderate vacuum of 100 mm to 28 mm of Hg in a yield of29.2 g.

The crude methyl 4-formylpentanoate obtained above was purified bydistillation at 83° to 85° C. at 6 mm to 8 mm of Hg with 90% recovery.Purity by GLC after distillation was determined to be 95.3% and theproduct was characterized by IR, NMR and GC/MS.

¹³ C NMR in d₆ --DMSO (in δ units):51.4 (--COOCH₃); 173.2 (--COOCH₃);31.0 (--CH₂ --COOCH₃); 25.4 (--CH₂ --CH₂ --COOCH₃); 45.1 (CH--CH₃); 13.0(CH--CH₃); and 204.7 (--CHO).

EXAMPLE 6

To a sample of 53.2 g (0.19 m) of undistilled morpholino cyclobutaneester prepared as in Example 4 was added with stirring at 26° C. 46.3 ml(0.19 equivalents) of 4.1 Normal H₂ SO₄. The temperature rose to 42° C.and the reaction mixture was then heated to 98° C. and held under refluxfor 3.5 hours to produce a two-phase reaction product. The upper layerwas separated, diluted with 25 ml of methylene chloride and extractedtwice with water, 25 ml each. Vacuum evaporation of the methylenechloride yielded 25.6 g of methyl 4-formyl pentanoate which was 87.5%pure by GLC.

EXAMPLE 7

To a sample of 103.6 g (0.41 m) of morpholino cyclobutane carboxylateester prepared as in Example 4 was slowly added with stirring an aqueousHCl solution made up of 41 ml of concentrated HCl mixed with 48 ml ofwater to result in 0.49 m of HCl. During the addition over 0.75 hours,the temperature rose to 70° C. and the reaction mixture was then heatedat 106° C. under reflux for 31/2 hours to yield a two phase reactionproduct. The upper layer was separated in a separatory funnel and thelower aqueous layer was extracted three times with methylene chloride,70 ml each. The combined extracts were washed once with 80 ml of water,vacuum evaporated and combined with the upper product layer yielding49.1 g of methyl 4-formylpentanoate which was 97% pure by GLC.

EXAMPLE 8 Step (b) to yield 5-methyl-3,4-dihydro-2(1H)pyridone offormula (V)

To 1.44 g (0.01 m) of methyl 4-formylpentanoate dissolved in 10 ml ofacetic acid was added 1.54 g (0.02 m) of ammonium acetate and themixture was heated at 80° to 125° C. for 16 hours. GLC showed about 11%unreacted starting material, 89% of the desired title product and noby-products. The product was vacuum stripped, dissolved in 10 ml ofethyl acetate and washed 4 times with water, 2.5 ml each wash. Theproduct was distilled after vacuum stripping of ethyl acetate to yield0.5 g of 5-methyl-3,4-dihydro-2(1H)pyridone, bp 103° C. at 0.5 mm of Hg.The product was recrystallized from ethyl acetate, mp, 76° to 78° C.

Elemental Analysis: N, 12.13% (Calculated 12.8%).

¹³ C NMR in d₆ --DMSO (in δ units):19.0 (CH₃); 169.0 (C═O); 30.1 (CH₂ αto C═O); 25.5 (CH₂ β to C═O); 112.0 (C(CH₃)═CH); and 120.3 (CH directlyattached to NH)

EXAMPLE 9

The procedure of Example 8 was repeated utilizing 33.7 g (0.234 m) ofmethyl 4-formylpentanoate, 36 g (0.467 m) of ammonium acetate and 200 mlof acetic acid at 105° C. with a reaction time of 22 hours. The productwas vacuum stripped at 65° to 95° C. bath temperature at 10 mm of Hg and200 ml of distillate were collected. The residue was dissolved in 200 mlof toluene and washed four times with 50 ml of water each time. Theaqueous extracts were washed two times with 70 ml of toluene each timeand the combined toluene extracts were vacuum stripped at 40° to 50° C.at 80 to 100 mm of Hg. The yield of 5-methyl-3,4-dihydro-2(1H)-pyridonewhich solidified at room temperature was 13.6 g (52% yield).

EXAMPLE 10

A neat reaction was conducted to yield5-methyl-3,4-dihydro-2(1H)pyridone by mixing 10 g (0.0693 m) of4-formylpentanoate and 10.7 g (0.139 m) of ammonium acetate at roomtemperature followed by stirring and heating to 100° to 110° C. for 1.5hours. A fairly vigorous reaction occurred at 95° C. with bubbling andrelease of some NH₃. After four washings of the residue with 10 to 15 mlof chlorobenzene, the product was shown in the chlorobenzene to have ayield of 73% by GLC.

EXAMPLE 11

A sample of 5 g (0.0347 m) of 4-formylpentanoate was stirred with 3.57 g(0.045 m) of ammonium bicarbonate and heated to 40° C. To the mixturewas gradually added 3 g (0.05 m) of acetic acid at 41° to 45° C. over 35minutes while the initial foaming disappeared. The clear solution washeated at 92° to 97° C. for 2 hours to yield 9.28 g which was distilledat a bath temperature of 100° to 122° C. at about 1 mm of Hg vacuum toyield 2.14 g of the compound of formula (V) which was 98.5% pure by GLCanalysis.

EXAMPLE 12

To 5.4 g of 4-formylpentanoate was added 5.6 g (a 95% excess) ofammonium acetate and 50 ml of ethanol. The reaction was carried out at30° C. for 5 hours and the ethanol was then vacuum stripped after 16hours at room temperature. The product was partitioned in 30 ml tolueneand 10 ml of water, the water layer was discarded and the toluene layerwas refluxed at 82° to 88° C. for 3 hours. The product was obtained byvacuum evaporation of the toluene and the purity of the5-methyl-3,4-dihydro-2(1H)-pyridone was 81% by GLC.

During this reaction, a reaction intermediate, probably the methyl4-iminopentanoate, was detected by GLC when the reaction was carried outfor only 10 minutes to 1 hour.

EXAMPLE 13

To 6.0 g (0.0416 m) of methyl 4-formylpentanoate in 15 ml of absoluteethanol is added 10.5 g of a NH₄ OH solution (prepared from 33.3 g of a30% NH₄ OH solution and 100 ml of water). The reaction was carried outat room temperature for 20 hours followed by vacuum stripping at 30° to55° C. under a moderate vacuum of about 200 to 40 mm of Hg. Distillationof the product under forcing conditions of a pot temperature of 125° to130° C. at a pressure of 1 mm of Hg gave a fraction distilling at 100°to 110° C. which was identified as 5-methyl-3,4-dihydro-2(1H)pyridone.The product was 95.3% pure by GLC.

EXAMPLE 14

A solution of 5 g of methyl 4-formylpentanoate in 15 ml of chlorobenzenewas slowly added to a solution of 3.0 g of ammonium acetate in 15 ml ofchlorobenzene which is then held at 90° to 100° C. The volatiles wereallowed to distill during the reaction so that the temperature could bemaintained at 98° C. for 1.5 hours after the addition. Gradually,clearing took place during the 1.5 hours and GLC of the product showedonly 5-methyl-3,4-dihydro-2(1H)pyridone and a small amount of startingmaterial. Distillation yielded the desired products as a whitecrystaline solid in 90% yield.

The above reaction was repeated using 3.1 g of ammonium bicarbonate and2.6 g of acetic acid in the place of the ammonium acetate.

EXAMPLE 15

To a reaction vessel was charged 380 ml of chlorobenzene followed by 67g (1.11 m) of glacial acetic acid. To the vessel was then added 63.5 g(1.12 m) of ammonium hydroxide in the form of a concentrated aqueoussolution over 5 minutes at 25° to 37° C. while stirring and cooling withan ice bath. The temperature was then raised to 90° C. at which pointthe addition of a solution of 127 g (0.88 m) of methyl4-formylpentanoate in 254 ml of chlorobenzene was started. The methyl4-formylpentanoate was added over 40 minutes while the temperature washeld at 90° to 96° C. The reaction mixture was two-phased and wascontinuously heated at 90° to 95° C. while volatiles were allowed todistill off. One hour after complete addition, GLC analysis showedlittle unreacted pentanoate and after two hours, only about 2% wasunreacted. The product was isolated by vacuum stripping of chlorobenzeneat a pot temperature of 60° to 85° C. with a final vacuum of 20 mm ofHg. The product of formula (V) was then distilled at a pot temperatureof 100° to 150° C., a vapor temperature of 93° to 113° C. at about 1 mmof Hg. The yield of formula (V) as a yellow solid was 83.6 g (0.75 m)which was 99% pure by GLC (85% yield).

EXAMPLE 16 Steps (a) and (b) to yield5-methyl-3,4-dihydro-2(1H)-pyridone of formula (V) via acrylamide offormula (III) (Y═CONH₂)

A sample of 25 g of morpholinopropene of the formula (VII) was dissolvedin 80 ml of acetonitrile at room temperature and treated with a warmsolution of 39.1 g of acrylamide in 100 ml of acetonitrile dropwise at areaction temperature of 25° C. The temperature was then raised to 80° to85° C. and held there for about 40 hours. The product was filtered hotto remove a small amount of insoluble matter and was then treated with asolution of 12 g of glacial acetic acid in 80 ml of water at 75° to 80°C. for 6.5 hours. The product was vacuum-stripped at 48° C. undermoderate vacuum to remove acetonitrile and the residue was washed withtoluene and ethyl acetate. GLC of the aqueous solution showed acomposition of about 2:1 acrylamide:aldehyde of formula (IV) (Y═CONH₂).The aqueous solution was vacuum-stripped at 50° to 60° C. under 40 mm ofHg pressure to leave the product as a light amber viscous residue. Thiswas treated with 100 ml of ethanol, crystallized and filtered to removepart of the acrylamide. Final vacuum-stripping gave 58.9 g of residueconsisting of acrylamide and 4-formylpentanamide. The product of formula(V) was generated thermally from this product by treatement at 100° to140° C. under high vacuum. During this treatment, 12.5 g of distillatewas produced comprising the compound of formula (V) and acrylamide.Remaining was 35 g comprising compound (V) and morpholinopropionamide.GLC analysis showed that the distillate contained about 40% by weight(V) while the residue contained 20% (V). Addition of acetonitrile to thedistillate and hot ethyl acetate to the residue gave acrylamide as acrystalline solid, mp 76° to 80° C. from the distillate andmorpholinopropionamide, mp 94° to 100° C. as a crystalline solid fromthe residue. The compound of formula (V) was found in the solutionsafter crystallizations to the extent of about 60%.

EXAMPLE 17 Step (b), stages (iv) and (v) to yield the pyridone adduct offormula (X) as an intermediate and 5-methyl-3,4-dihydro-2(1H)pyridone offormula (V) as a final product.

To 2.0 g of methyl 4-formylpentanoate was added with stirring 9 ml ofconcentrated ammonium hydroxide solution gradually and an exothermicreaction took place with a temperature rise from 25° to 55° C. After 1/2hour, GLC showed 99% product and the temperature was then held at 88° to96° C. for 1 additional hour and the product was then vacuum stripped at80° C. under a pressure of 5 to 20 mm of Hg for 1/2 hour. Although theGLC analysis showed product with a very high purity, the NMR analysisdetermined that no 5-methyl-3,4-dihydro-2(1H)pyridone was present. Theconclusion reached is that an intermediate was prepared which convertedto the desired product under GLC injection conditions. Isolation of theintermediate was carried out by crystallization with 3 ml of ethylacetate. The yield of several fractions was 25% as a crystaline whitesolid, mp, 158° to 166° C. The compound was insoluble in ethanol,acetone and toluene but soluble in methylene chloride. The product wasdissolved in a hot mixture of 7 parts by volume of methanol and 9 partsby volume of ethyl acetate and recrystallized to give an mp of 182° to184° C.

Elemental Analysis: N, 17.0% (Calculated for the compound of formula (X)as C₁₂ H₂₁ N₃ O₂, N, 17.55%).

¹³ C NMR in CDCL₃ (shift of +77.0 ppm using CDCL₃ as the standard) (in δunits):174.6, 173.4 (C═O); 31.3, 30.6 (CH₂ --C═O); 26.3, 23.3 (CH₂ --CH₂--C═O); 35.8, 33.3 (CH--CH₃); 75.3, 71.0 (NH--CH--NH): and 17.9, 17.7(CH₃).

EXAMPLE 18

The high-melting intermediate prepared in Example 17 was prepared undermilder conditions by treating 2 g (0.014 m) of 4-formylpentanoate in 5ml of absolute ethanol with 3.5 g (0.02 m) of dilute NH₄ OH solution(prepared from 33.3 g of a 30% NH₄ OH solution and 100 ml of water) atroom temperature. GLC samples taken during the reaction showed a mixtureof starting material, the desired product peak due to the intermediateof formula (X) and methyl 4-iminomethylpentanonate. After 24 hours atroom temperature, the major peak was the product. The reaction mixturewas vacuum evaporated at 60° C. under 1 to 6 mm of Hg to give 1.5 g ofproduct which was recrystallized from 3.5 ml of ethyl acetate, mp 171°to 174° C.

The product of formula (X) was recrystallized from excessacetone/methanol to yield crystals, mp 178° to 182° C.

Elemental Analysis: C, 59.85% (Calculated 60.2%); H, 8.63% (Calculated8.85%): N, 17.58% (Calculated 17.55%).

EXAMPLE 19 Step (c), stages (vi) and (vii) to yield the dihalo compound(IX) (X¹ ═Cl) as an intermediate and pyridone (VI) as a final product.

A solution of 1.5 g (0.0135 m) of 5-methyl-3,4-dihydro-2(1H)pyridone offormula (V) in 9 ml of chloroform was treated with sulfuryl chloridedropwise at 25° to 33° C. After 1 hour at 30° C., a GLC in ethanolsolution (with potassium hydroxide) showed conversion of the startingmaterial to the chloro ethoxy adduct indicating reaction of chlorineacross the double bond with no starting material. After 2 hours at 33°C., the product was vacuum stripped at 15° to 45° C. over a period of 3hours gradually reducing the pressure from 200 to 15 to 30 mm of Hg. Theyield was 2.63 g of a colorless amorphous product of the formula (IX)wherein X¹ is chloro. A sample of 2.32 g of this product was stirredwith magnet for 1.5 hours at a bath temperature of 132° to 138° C. under12 to 35 mm of Hg. The yield was 1.57 g of product of the formula (VI)as the hydrochloride and free base.

The free base of the compound of formula (VI) was generated by adding 4ml of water followed by 0.4 g of sodium carbonate to the productproduced in the above paragraph to result in a pH of 9 and vacuumstripping followed with recovery of the pyridone of formula (VI) bywashing the residue with warm acetone to yield 0.53 g of the compound offormula (VI) in the acetone, mp, 150° to 172° C. Preferably, theextraction with warm acetone is replaced by an ethanol extraction.

In a similar example, the product was recrystallized from methanol toyield a product with a melting point of 178° to 180° C.

EXAMPLE 20

The procedure of Example 19 was repeated utilizing 5 g of the startingmaterial of formula (V). The free base was generated with 15 ml of waterand 1.7 g of sodium carbonate at a pH of 8.5 and the mixture was thenvacuum stripped to remove water. The residue was washed with hot ethanoland the ethanol was then vacuum stripped to yield the product of formula(VI), mp 119° to 147° C.

EXAMPLE 21

The procedure of Example 19 was repeated with the substitution ofchlorobenzene, also known as monochlorobenzene, for chloroform asfollows. The reaction was carried out using 4 g of the product offormula (V), 8 ml of chlorobenzene and 4.4 ml of sulfuryl chloride ofthe formula SO₂ CL₂ (a 50% excess). The dropwise addition of sulfurylchloride was carried out at 23° to 38° C. with slight cooling followedafter one hour by application of a vacuum of 75 to 150 mm of Hg at 27°to 38° C. for 1 hour. The temperature is then raised to 129° C. in thepot and 141° to 143° C. in the oil bath at a pressure not less than 220mm of Hg for 3 hours. The product precipitates out as a fairly fluidlower layer during the reaction, is quite viscous on cooling andconsists of the compound of formula (VI), partly in the form of thehydrochloride salt.

EXAMPLE 22

Into a solution of 7.0 g of the compound of formula (V) in 35 ml ofchlorobenzene at 20° C. was introduced 7 g of chlorine gas over a periodof 30 minutes. This solution was added gradually over 1 hour to 15 ml ofchlorobenzene at 130° C. while nitrogen was bubbled through thesolution. After addition, the reaction was continued for 4 hours as theproduct precipitated. To the product was added 18 ml of water and theproduct mixture was neutralized to a pH of 8.5 in the aqueous phase with5 ml of 5 Normal NaOH. After vacuum stripping, the product was dissolvedwith ethanol and diluted to a volume of 100 ml. This solution wasanalyzed by GLC and found to contain 5.4 g of the compound of formula(VI) (78.6% yield).

EXAMPLE 23 Steps (c) and (d) to yield compound (I) (X═Cl) withoutisolation of pyridine (VI)

A sample of 4 g of crystallized 5-methyl-3,4-dihydro-2(1H)pyridone offormula (V) was dissolved in 8 ml of chlorobenzene and was treated with4.4 ml of sulfuryl chloride as described in Example 20. Afterdehydrohalogenation at 129° C., the product consisted of a lower darkproduct phase which was very viscous at 40° C. To the slurry of bothphases was added 10.4 ml of POCl₃ at 40° over 1/2 hour followed by 3.4 gof phosphorous pentachloride. The mole ratio of the product of formula(VI):POCl₃ :PCl₅ was 1:3:0.45. The reaction mixture became homogenousand was heated at 116° to 118° C. for 4 hours. To the product was thenadded to 50 g of crushed ice, 50 ml of chlorobenzene and 162 ml of a 13%aqueous sodium hydroxide solution. Phase separation was made in aseparatory funnel and the lower aqeuous layer was extracted 3 times with20 ml of chlorobenzene each. The product layer and chlorobenzeneextracts were combined and analyzed by GLC. The thus-producedchlorobenzene solution contained 1.5 g of the product of formula (I)wherein X is chloro.

EXAMPLE 24

Into a solution of 7.0 g of the compound of formula (V) in 35 ml ofchlorobenzene was introduced 8.0 g of chlorine gas at 20° over a periodof 1.25 hours. This solution was added gradually to 15 ml of stirredchlorobenzene held at 130° C. over a period of 1 hour. The reaction wascontinued at 130° C. for 4.5 hours and the product slurry was cooled to60° C. To this was then added 14.5 g of POCl₃ dropwise over 15 minutesfollowed by 2.62 g of PCl₅ also at 60° C. The reaction mixture washeated to 115° C. for 4.5 hours. For the purposes of analysis, theproduct was added to 40 ml of methanol, vacuum stripped at 50° C. at 130mm of Hg and the addition of methanol and vacuum stripping was repeated.The product was then neutralized to a pH of 6 with 45 ml of alcholic KOHsolution, prepared from 16 g of KOH in 100 ml of methanol, and dilutedto 100 ml with methanol. The product solution was analyzed by GLC andwas found to contain 4.85 g of the compound of formula (I) wherein X ischloro.

EXAMPLE 25 Step (d) to yield compound (I) (X═Cl)

To 4.2 g of the compound of formula (VI) was added 15 ml of POCl₃ at 25°to 34° followed by 3 g of PCl₅. The reaction mixture was stirred andheated at 110° C. for 4 hours and gradual solution took place. Theproduct was added to 100 g of crushed ice and neutralized to pH 8 with80 ml of 15% sodium hydroxide while cooling. The aqueous solution wasextracted 5 times with 24 ml of methylene chloride each. The extractswere analyzed by GLC and evaporated at 40° C. at 4 mm of Hg to aconstant weight. The yield was 3.9 g of the compound of formula (I)wherein X is chloro.

Elemental Analysis: Cl, 26.55% (Calculated, 27.8%); N, 10.75%(Calculated, 10.98%).

The GLC retention times and NMR of the product were identical to thoseof authentic samples of the compound of formula (I) wherein X is chloro.

EXAMPLE 26

In the above Example 25, separations of the product phase from theaqueous phase may be difficult and incomplete if the product phase istoo concentrated. A more dilute system is believed to be more practicalas described below.

The procedure of Example 25 was repeated with a 1:1 (w:w) dilution(weight:weight of the compound of formula (VI) with chlorobenzene. Asample of 3.0 g of compound (VI) was mixed with 3 g of chlorobenzene and4 ml of POCl₃ were added gradually at 25° to 32° C., followed by 2.6 gof PCl₅ at 27° to 32° C. The slurry was heated to reflux and held at117° to 119° C. for about 4 hours. The product was cooled to roomtemperature and added to 50 g of ice, diluted with 17 ml ofchlorobenzene and neutralized to a pH of 8.0 with a 15% NaOH aqueoussolution. The chlorobenzene solution was separated in a separatoryfunnel as the lower layer. The upper layer was diluted with 30 ml ofwater and extracted two times with 10 ml of chlorobenzene each. Thecombined chlorobenzene solutions were analyzed by GLC to indicate 2.9 gof compound (I) wherein X is chloro.

EXAMPLE 27

To 50 ml of toluene at 8° C. was added 10 g of phosgene under a nitrogenblanket. The solution was heated to 45° C. and a warm solution of 4 g ofthe compound of formula (VI) in 10 ml of dimethylformamide was addeddropwise over 18 minutes with foaming and precipitation. The reactionmixture was stirred and heated to 56° C. over 2 hours. The productmixture was then cooled and mixed with 4 ml of water and neutralizedwith 20 ml of dilute NH₄ OH (produced from 80 ml of concentrated NH₄ OHdiluted with water to 100 ml) and 2 g sodium carbonate to a pH of 8.Phase separation was made in a separatory funnel and the upper phase wasvacuum stripped at 45° C. and a pressure of 65 mm of Hg to yield 1.9 gof the compound of formula (I) where X is Cl.

EXAMPLE 28 Step (c) to yield (XI) (X² ═Cl).

A solution of 0.5 g of the compound of formula (V) in 3 ml of toluenewas treated gradually over 20 minutes at 25° to 40° C. with 0.55 ml ofSO₂ Cl₂ while stirring. The solution was then heated at 62° to 75° C.for 2 hours. The product was vacuum stripped over 1.75 hours at a bathtemperature of 60° C. down to a pressure of 12 mm of Hg. The yield was0.86 g of product. The product was extracted with 4 ml of warm tolueneleaving 0.26 g of toluene-insoluble product. Of the insoluble product,0.2 g was dissolved in a hot solvent mixture of 1 ml of acetone and 0.5ml of cyclohexane which crystallized at room temperature. The yield ofcompound of formula (XI) was 0.11 g, mp 135° to 142° C. Characterizationwas made by MS and Elemental Analysis.

EXAMPLE 29 Step (c) to yield (XII) (X³ ═Cl).

A solution of 0.5 g of the compound of formula (V) in 3 ml of chloroformwas stirred and treated at 28° to 36° C. gradually with 0.55 ml of SO₂Cl₂. The solution was heated to 62° to 65° C. and precipitation ofproduct occurred at that temperature. The solution was cooled to roomtemperature and filtered. The product was washed two times with 2 mlchloroform each. The yield was 0.26 g of product, mp 157° to 159° C. Thechloroform washes where vacuum stripped to obtain 0.53 g of additionalproduct. The product obtained was the hydrochloride salt of the compoundof formula (XII) wherein X³ is chloro as shown by MS, NMR and ElementalAnalysis. After washing with hot acetone, the purified product had an mpof 160° to 162° C.

What is claimed is:
 1. 5-Methyl-3,4-dihydro-2(1H)pyridone of thefollowing formula (V): ##STR13##
 2. A method of preparing thedihydropyridone of the following formula (V): ##STR14## comprising thesteps of: (a) reacting propionaldehyde of the following formula (II) ina Michael addition with an acrylic compound of the following formula(III): ##STR15## wherein Y is a moiety of the formula --COOR, --CONH₂ or--CN and R is alkyl of about 1 to 6 carbon atoms, aryl of about 6 to 10carbon atoms, arylalkyl of about 1 to 8 carbon atoms in the alkylportion and about 6 to 10 carbon atoms in the aryl portion which may belower alkyl- or halo-substituted in the aryl or aryl portion, to producean aldehyde of the following formula (IV): ##STR16## and (b) cyclizingthe aldehyde of formula (IV), adding an amine or ammonium salt when Y isCOOR.
 3. The method of claim 2, wherein step (a) is conducted in threestages which comprise:(i) reacting propionaldehyde with a secondaryamine of the formula HNR¹ R², wherein R¹ and R² are lower alkyl groupsof about 1 to 6 carbon atoms or R¹ and R² are joined together to formwith the N atom a 5- or 6-membered heterocyclic ring, to form theenamine of the following formula (VII): ##STR17## (ii) reacting theenamine of formula (VII) with the acrylic compound of formula (III) toform the compound of the following formula (VIII): ##STR18## and (iii)hydrolyzing the compound of formula (VIII) to the aldehyde of formula(IV).